Cervical Cancer
Cervical cancer is one of the most common cancers in women worldwide. Nearly all invasive squamous cell carcinomas are preceded by persistent human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN), and vast improvements in screening over the last 60 years have dramatically lowered the incidence of invasive disease in the developed world. Localized and some advanced cervical cancers in the United States have excellent prognoses, yet in developing countries, this disease remains the most lethal malignancy in women.
EPIDEMIOLOGY
Key Points
1. Minority and low-socioeconomic status patients are still at risk for developing cervical cancer in the United States due to lack of screening and early treatment.
2. The largest risk factor for cervical cancer is persistent HPV infection. Other risk factors include history of sexually transmitted diseases, multiple sexual partners, high parity, immunosuppression, and smoking.
3. The HPV oncoproteins E6 and E7 bind and inactivate the tumor suppressor genes p53 and pRB, respectively, which contributes to cervical carcinogenesis.
Incidence
Cervical cancer is the third most common cancer in women worldwide, with more than 450,000 cases diagnosed annually. Developed countries have demonstrated a decreasing incidence and mortality from squamous cervical cancers over the last 50 years. This is likely due to improved access to screening, decreasing parity, and lower baseline prevalence of HPV. Adenocarcinomas of the cervix account for approximately 15% of cervical cancers in the United States and have risen slightly over the last 20 to 30 years. The recent availability of an HPV vaccine has been shown to decrease the incidence of high-grade CIN and may further reduce the incidence of cervical cancer in years to come.1
In 2010, the American Cancer Society estimates 12,200 new cases of cervical cancer in the United States, with 4210 women predicted to die from this disease. The peak incidence for this disease is 45 years. Although the overall incidence of cervical cancer is low in the United States, the incidence in African Americans is nearly 50% higher than in Caucasians, and the incidence in the Hispanic population is more than double that of Caucasians. Furthermore, in comparison with Caucasians. African Americans are more frequently diagnosed with advanced-stage tumors and are less likely to receive treatment.2
Risk Factors
Several established risk factors are known to contribute to cervical carcinogenesis. More than 99% of cervical cancers are associated with infection with HPV; risk factors associated with HPV infection are the same for CIN and cervical cancer. These include multiple sexual partners, history of other sexually transmitted infections, high parity, immunosuppression, and cigarette smoking.3 Obesity has been associated with a slightly increased risk of adenocarcinoma of the cervix.4 However, neither parity nor smoking has been associated with increased risk of adenocarcinoma of the cervix.5 Interestingly, although cervical cancer is not a typical genetically inherited disease, it does tend to aggregate in families.6
Women who smoke have a dose-dependent increased risk of having persistent HPV. Cigarette smoking may contribute to the development of high-grade cervical dysplasia in women with underlying HPV infection.7 This may be due to genotoxicity secondary to the presence of tobacco-derived carcinogens in cervical secretions. Cigarette smoking has also been found to have immunosuppressive effects and may predispose patients to persistent HPV infection.
High parity has been associated with increased rates of cervical cancer and dysplasia, although the mechanism is not clear.8 Oral contraceptives are a difficult variable to study in regard to HPV infection, because of the difficulty in separating sexual habits and contraceptive use. However, one large multicenter case-control study and several meta-analyses revealed that women taking oral contraceptives may have an elevated risk of invasive cervical cancers.3,9,10 Parity has also been found to be an independent risk factor, potentially secondary to cervical trauma.11 Additionally, coinfection with Chlamydia trachomatis has also been associated with HPV persistence, cervical neoplasia, and cervical cancer.12
Several protective behaviors have been identified as well. Consistent condom use has been associated with a partial protective effect against HPV infection and cervical dysplasia.13 Additionally, circumcision has been associated with reduced HPV detection in males, and wives of men with multiple sexual partners have been found to have higher rates of cervical cancer.14
Patients infected with human immunodeficiency virus (HIV) commonly have concurrent HPV infections. In patients HIV-associated immunosuppression, abnormal cervical cytology rates may be as high as 78%.15 Increased incidence of abnormal cervical cytology has been correlated with low CD4+ lymphocyte counts, but not with duration of HIV infection, antiretroviral therapy, or viral load.16
Pathogenesis
The malignant transformation of cervical cells is intimately related to HPV infection. HPV is an extremely common, double-stranded DNA virus acquired by sexual contact. HPV infects basal keratinocytes and replicates during keratinocyte differentiation. More than 100 types of HPV have been sequenced, and many more have been partially characterized. Of these, approximately 40 infect the genital tract, and these are responsible for condylomata, some hyperproliferative lesions, and dysplastic lesions of the cervix, vulva, vagina, and anus. In the United States, HPV16 is the most carcinogenic type, and genotypes 16 and 18 have been associated with nearly 70% of cervical cancers worldwide.17 In particular, HPV18 accounts for approximately 50% of adenocarcinomas, as compared with only 15% of squamous cell carcinoma.18
All papillomaviruses have regulatory, early (E), and late (L) genomic regions. Early proteins are required for replication and/or cellular transformation. These include proteins E6 and E7, the major HPV oncoproteins. The E6 protein binds specifically to E6-AP, which associates with the tumor-suppressor protein p53, causing rapid degradation. Loss of p53 results in failure of growth arrest and loss of appropriate apoptotic signaling in response to cell damage. E7 interacts with the retinoblastoma tumor suppressor gene (pRb), which normally complexes with E2F transcription factors. Formation of E7-pRb complexes disrupts the pRB-E2F complex, which initiates cell growth. E7 is able to immortalize keratinocytes independently, but the combination of E6 and E7 in transgenic mice have been found to result in aggressive invasive cancers.19
HPV genomes initially infect the cell in circular extrachromosomal copies. Over time, however, the HPV viral genome can become inserted into host cell DNA in a process called integration. Integrated HPV has been found to be present in 83% of invasive cervical cancers, as compared with 8% of low-grade squamous epithelial lesions, suggesting that integration may be associated with the transition of low-grade to high-grade lesions.20 Once integration has occurred, E6 and E7 transcription is not downregulated by the viral regulatory protein E2, and intracellular E6 and E7 oncoprotein levels increase. Keratinocytes that express E6 and E7 are immortalized and may ultimately become tumorigenic.
DIAGNOSIS
Key Points
1. Early-stage cervical cancers are frequently asymptomatic; advanced-stage disease may present with malodorous or bloody vaginal discharge, back pain, hematuria, or rectal bleeding.
2. Cervical cancer staging according to the International Federation of Gynecology and Obstetrics (FIGO) system is performed clinically and may only include such radiographic studies as chest radiograph, intravenous pyelogram, or barium enema.
Clinical Features
The majority of women with early-stage cervical cancers are asymptomatic and are typically diagnosed after evaluation of an abnormal screening Pap smear. For patients with large tumors or advanced-stage disease, the most common presentation is abnormal vaginal bleeding, particularly after intercourse. With tumor growth and necrosis, patients may have additional complaints of malodorous vaginal discharge. In advanced cases, cervical cancer can also cause pelvic pressure and pain or bleeding with urination or defecation. Meta-static disease may cause difficulties with radiating or neuropathic pain, or lower-extremity edema.
On physical examination, the most common finding is a cervical lesion, which should be biopsied. Cervical cancer is clinically staged, and the examination is critical for treatment planning. For this reason, examination should include a detailed description of the size (depth and width) of the primary cervical lesion, as well as documentation of a rectovaginal examination to evaluate for potential parametrial and pelvic sidewall extension. Additionally, regional and distant lymph nodes should be examined for potential metastases; these include the superficial groin and femoral nodes, as well as supraclavicular nodes.
Diagnostic Testing
Diagnostic tests may be included in the clinical staging of cervical cancer; these are limited to standard chest radiography, intravenous pyelogram, and barium enema. Chest radiography may identify metastatic lesions to the lungs, whereas intravenous pyelogram can determine hydronephrosis, suggesting metastatic disease to the pelvic sidewall. Barium enema is useful when patients report rectal bleeding; it can identify metastases to the recto-sigmoid colon.
Although findings from additional imaging tools such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) are not formally included in the staging system, they may supplement clinical suspicion of parametrial and sidewall disease and influence treatment planning. Of these techniques, MRI is the most sensitive for detecting locally advanced disease. A prospective collaborative trial sponsored by the American College of Radiology Imaging Network and the Gynecologic Oncology Group (GOG) demonstrated a sensitivity of 53% with MRI compared with 29% for clinical staging and 42% for CT.21 Furthermore, the negative predictive value of MRI in detecting parametrial invasion is 95%.22 It is more difficult to determine parametrial invasion based on MRI, and positive predictive value remains significantly lower; this is due to the similarity of the radiographic appearance of parametrial tissue and cervical tumor.23 In addition, PET imaging may identify lymph nodes suggestive of metastatic disease. PET imaging rapidly evaluates metabolic activity, therefore using physiologic processes rather than the anatomic changes detected by conventional radiography. Fusion of CT and PET images has high sensitivity and specificity in detecting lymph node metastases.24,25
Diagnostic Procedures
Several diagnostic procedures are pertinent in the diagnosis of cervical cancer. Small cancers may be identified after cervical conization or loop electrosurgical excision for dysplasia. Because this disease is not staged surgically, operative findings such as lymph node metastases do not influence the staging system. However, examination under anesthesia with cystoscopy and proctoscopy should be considered when office examination is limited due to anatomic distortion from tumor or patient discomfort or when suspicion for bladder or rectal involvement is high.
Role of the General Gynecologist
Primary care providers, including family medicine physicians, internists, obstetrician/gynecologists, as well as physician assistants and nurse practitioners, play a critical role in cervical cancer screening, cervical dysplasia management, and establishing the diagnosis of cervical cancer. The American Cancer Society, American Society for Colposcopy and Cervical Pathology, United States Preventative Services Task force, and the American Congress of Obstetricians and Gynecologists provide regularly updated screening guidelines and recommendations for the general practitioner, which are detailed in Chapter 4. Procedures commonly used by the general obstetrician/gynecologist include colposcopy, cervical biopsy, and cervical conization procedures in the management of cervical dysplasia; once a formal diagnosis of cervical cancer is made, referral should be made to a gynecologic oncologist for definitive treatment planning.
PATHOLOGY
Key Points
1. The majority of cervical cancers are of squamous histology and spread via direct extension.
2. Adenocarcinomas constitute a smaller percentage of cervical cancers, but both the overall incidence and proportion of adenocarcinomas of the cervix appear to be rising.
3. Stage IA1, or microinvasive carcinoma, is defined by a depth of invasion less than 3 mm and a lesion width no greater than 7 mm.
Histopathology
Squamous Cell Carcinoma
The majority of cervical cancers are of squamous cell histology (Table 5-1). Squamous cell cancers develop after an interval of preinvasive disease, as discussed in Chapter 4. Dysplastic cells are characterized by an increased nuclear-to-cytoplasmic ratio and have prominent mitotic figures. CIN can progress to carcinoma in situ, with subsequent invasive disease identified after penetration of dysplastic cells through the basement membrane (Figure 5-1).
FIGURE 5-1. Demonstration of the progression of cytologic atypia. (A) Normal cervical epithelium; (B) cervical intraepithelial neoplasia (CIN) 1; (C) CIN2; (D) CIN3; (E) adenocarcinoma in situ.
Table 5-1 Histologic Subtypes of Cervical Cancer
Grossly, squamous cell cervical cancers can exhibit a heterogeneous appearance, ranging from small nodular lesions to large, bloody friable tumors with malodorous exudate. Microscopically, cervical cancers demonstrate infiltrative nests of cells with eosinophilic cytoplasm and large, hyperchromatic nuclei. There is frequently a desmoplastic stromal response surrounding the nests of carcinoma. Mitoses are frequently numerous. Lesions may be further characterized as keratinizing or nonkeratinizing, depending on the presence of keratin pearls (Figure 5-2). They are also graded; grade 1 tumors are well differentiated and uncommon. They have mild atypia, large numbers of keratinized cells, and scant mitotic figures. Grade 2 tumors are more common and are largely nonkeratinizing with numerous mitoses, pleomorphic nuclei, and an infiltrative pattern. Grade 3 tumors are poorly differentiated and are pleomorphic with anaplastic nuclei and a tendency to form spindle cells and may be difficult to distinguish from sarcomas without cytokeratin staining.
FIGURE 5-2. Invasive squamous cell carcinoma of the cervix. (A) Nonkeratinizing invasive carcinoma; (B) keratin pearls.
There are several rare histologic variants of squamous cell carcinomas of the cervix that include verrucous, papillary squamotransitional, warty, and lymphoepithelioma-like carcinomas. Verrucous carcinomas appear grossly as a large, sessile tumor that may be confused for condyloma acuminatum. Clinically, verrucous carcinoma behaves in a slow-growing, locally invasive fashion; however, it rarely involves regional lymph nodes or distant metastases. Histologically, verrucous carcinoma of the cervix is characterized by frond-like papillae, which may be keratinized, without a connective tissue core. In order to make the correct diagnosis, the base of the tumor must be evaluated, as superficial layers frequently lack atypia or frequent mitosis. The basal layer is composed of well-circumscribed invasive nests of epithelium that invade the cervical stroma in a pushing fashion and have a characteristically inflammatory appearance at the base of the epithelium.
Papillary squamotransitional carcinoma may present with a variety of histologic appearances, but often demonstrate superficial papillary architecture with a connective tissue core. They may also have extensive mitoses, nuclear atypia, and keratinization. They may also display the multiple layers and oval-shaped, hyperchromatic nuclei typical of transitional cell carcinomas. Papillary squamotransitional carcinomas typically have immunohisto-chemistry markers of squamous differentiation. HPV16 has also been found in transitional cell carcinomas.26
Warty carcinoma is another rare variant of squamous cell carcinomas with marked condylomatous changes. They are associated with coinfection by several strains of HPV and have deep margins that demonstrate features typical of invasive squamous cell carcinoma.27 Many warty cell tumors also demonstrate notable cytoplasmic vacuolization. For this reason, they may be confused on cytology as low-grade koilocytosis.
Lymphoepithelioma-like carcinoma of the cervix is more common in Asian women and has been reported to have better prognosis than typical squamous cell carcinomas of the cervix. It has been associated with Epstein-Barr virus.28 Lymphoepithelioma-like carcinoma of the cervix is histologically similar to nasopharyngeal lymphoepitheliomas: The cells are poorly differentiated, with abundant cytoplasm and enlarged vesicular nuclei. Inflammatory cells including large numbers of T cells are prominent, and therefore, lymphoepithelioma-like carcinomas can be confused for glassy cell carcinoma (Figure 5-3). However, the cells tend to have indistinct cell borders that contrast with the distinctively bordered cells in glassy cell carcinomas.
FIGURE 5-3. Lymphoepithelioma-like carcinoma. Note abundant cytoplasm, enlarged vesicular nuclei, and infiltration of inflammatory cells. A. Low-power view shows prominent inflammatory cells. B. High-power view shows poorly differentiated cells with abundant cytoplasm and enlarged vesicular nuclei.
Adenocarcinoma
Adenocarcinomas are the second most common histo-logic type of cervical cancer. In contrast to squamous cell cancers, adenocarcinomas arise from the endocervical mucus-producing glandular cells. Grossly, the ectocervix may appear benign, but the cervix may be expanded or “barrel-shaped” given the disease in the endocervix. In contrast to squamous cell carcinomas, adenocarcinomas of the cervix may not be confluent and can exhibit so-called skip lesions. Histologically, foci of adenocarcinoma in situ or minimally invasive adenocarcinoma may be interspersed with areas of benign glands.
Endocervical-type mucinous adenocarcinomas are the most common subtype of cervical adenocarcinomas. Their cells resemble columnar cells found in normal endocervical mucosa. They are largely moderately to well-differentiated. The glandular elements may be arranged in a racemose, glandular pattern, appearing similar to the configuration of normal endocervical mucosa. Nuclei are basally located, but appear stratified with mitotic figures present. Endocervical mucinous adenocarcinomas may have uniform nuclei with minimal stratification. Well differentiated (grade 1) neoplasms demonstrate less than 10% solid components. Moderately differentiated (grade 2) disease displays increased mitotic figures, with solid components comprising up to half of the neoplasm. Poorly differentiated (grade 3) adenocarcinomas have more pleomorphic nuclei, mitoses, and may have a larger solid component, areas of marked desmoplasia, and necrosis (Figure 5-4).
FIGURE 5-4. Invasive adenocarcinoma of the cervix. (A) Well differentiated; (B) poorly differentiated.
There are also several histologic variants of cervical adenocarcinomas. Mucinous adenocarcinoma may contain goblet cells with intestinal differentiation. They may form glands with papillae or may demonstrate architecture similar to colonic adenocarcinoma. Glands may be lined by pseudostratified, malignant-appearing cells with intracytoplasmic mucinous vacuoles, goblet cells, or occasionally Paneth cells. Intestinal subtypes are extremely rare, and care must be taken to rule out metastatic disease from the gastrointestinal tract.
Minimal deviation adenocarcinoma is an uncommon, very well-differentiated form of cervical adenocarcinoma, previously referred to as adenoma malignum. Cells do not demonstrate features typical of malignancy. These tumors comprise approximately 1% to 3% of all cervical adenocarcinomas. They may be associated with mucinous adenocarcinomas and sex cord tumors of the ovary.29 They may occur as a sporadic neoplasm; however, they have also been associated with Peutz-Jeghers syndrome.30 However, they have not been associated with HPV infection. Clinically, minimal deviation adenocarcinomas may be associated with watery mucinous vaginal discharge or abnormal endocervical cells on cervical cytology. On physical examination, advanced tumors may appear as polypoid lesions and firm yellow neoplasms. Microscopically, glands are more infiltrative in appearance. Nuclei are bland and located at the base of the epithelium. In the endometrioid type, cells lining the glands resemble benign proliferative endometrium. Glands may appear similar to normal endocervical glands; however, they may vary in size or have atypical angular outpouchings surrounded by desmoplasia. Mitotic figures in benign endocervical glands are very rare; however, on high-power magnification, minimal deviation carcinoma can be noted to have mitoses. Therefore, one of the most reliable criteria is the depth of involvement of the cervical stroma. Whereas normal endocervical crypts are rarely deeper than 7 mm, minimal deviation carcinoma may extend through up to two-thirds of the cervical stroma29 (Figure 5-5). Immunochemistry has revealed that minimal deviation carcinoma may stain focally for carcinoembryonic antigen, and estrogen and progesterone receptors have been found to be uniformly negative in this disease.
FIGURE 5-5. Minimal deviation adenocarcinoma. A. Mitotic figures in benign endocervical glands are very rare; however, on high-power magnification, minimal deviation carcinoma can be noted to have mitoses. B. Deep invasive minimal deviation adenocarcinoma. Therefore, one of the most reliable criteria is the depth of involvement of the cervical stroma.
Villoglandular adenocarcinomas of the cervix are low-grade carcinomas that may appear similar to intestinal villous adenomas. Villoglandular adenocarcinoma of the cervix is characterized by low-grade atypia and rare mitotic figures. Histologically, these neoplasms have a long, filamentous, often inflammatory-appearing connective tissue core with an overlying layer of well-differentiated cells. They are frequently associated with high-risk HPV. Because these tumors may be associated with more aggressive carcinomas, the formal diagnosis should be made on cone biopsy. Villous adenocarcinomas tend to occur in young women, and unless associated with an underlying adenocarcinoma of poorer prognosis, these tumors have very good prognosis.31
Additional cervical adenocarcinomas include clear cell, papillary serous, and mesonephric tumors. Clear cell cancers are associated with intrauterine diethylstilbestrol exposure. Clear cell adenocarcinomas appear histologically as sheets of cells with atypical nuclei, mitotic figures, and abundant clear cytoplasm (Figure 5-6). Papillary serous carcinomas are morphologically similar to the more common papillary serous tumors of the ovary and endometrium and are not associated with HPV infection.32 Mesonephric neoplasms are a rare glandular subtype derived from wolffian duct remnants. Remnants of the mesonephric ducts are present in the lateral aspects of up to 20% of cervical specimen. They appear as small glandular structures with intraluminal Periodic acid-Schiff (PAS) stain–positive material. They are lined with cuboidal cells. Reti-form, tubular, and sex cord patterns have also been described. Patients may develop benign mesonephric hyperplasia of the cervix, and in 2 series of 49 and 14 cases, no consequences of disease were noted.33,34
FIGURE 5-6. Glassy cell carcinoma. A. Cells are large and polygonal, with eosinophilic, ground glass–type cytoplasm. B. Glassy cell carcinomas have abundant mitotic features, well-defined cell borders, and prominent infiltrate of eosinophils and plasma cells. C. High-power view.
However, mesonephric hyperplasia may be responsible for cervical cytology revealing atypical glandular cells. Histologically, it may be difficult to differentiate between benign mesonephric hyperplasia in the cervix and mesonephric adenocarcinoma, particularly because mesonephric carcinomas are likely to develop within areas of mesonephric hyperplasia.33
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